Although malaria has been treated for decades partly by eliminating any intermediate host with insecticides and partly by therapeutic measures, this infective illness caused by various types of Plasmodium even now constitutes one of the major health problems worldwide. It is estimated that, every year, up to 200 million people living in tropical countries are infected with malaria pathogens, with lethal consequences for 1 to 2 million of those affected (Sturchler, D., Experientia 40:1357-1362, (1984)).
The problem of fighting malaria is chiefly that, when insecticides are used, insecticide-resistant intermediate hosts or vectors (Anopheles) occur again and again and the drug treatment, which is basically only a prophylactic, constantly allows drug-resistant protozoa (Plasmodium) to develop (Doberstyn, E. B., Experientia 40:1311-1317, (1984); Bruce-Chwatt, L. J., Annu. Rev. Public Health 8:75-110, (1987)).
Ever since the start of modern malaria research, initiated over 100 years ago with the discovery of the original pathogen causing malaria (Laveran, A., Bull, Acad. Med. Paris 9:1235-1236, (1980)), it has not been possible to provide an active ingredient which provides an adequate and lasting therapy for malaria infection.
The bite of the infected mosquito causes malaria parasites (sporozoites) to be transferred to humans. These sporozoites colonize the liver where they multiply. At the end of this development phase, parasites (merozoites) enter the bloodstream and attack erythrocytes. With the infection of the erythrocytes, the actual clinical phase of the illness begins with the known symptoms and complications.
For the treatment of malaria in humans and animals, which has hitherto been of a purely prophylactic nature, a number of measures have been proposed which comprise the use of antimalarial substances, immunization or vaccination and the use of cytokines.
The known antimalarial substances can be divided into the following 6 main groups on the basis of their chemical compositions:
1. the 9-aminoacridines (e.g. mepacrine), PA0 2. the 4-aminoquinolines (e.g. amodiaquine, chloroquine, hydroxchloroquine). PA0 3. the 8-aminoquinolines (e.g. primaquine, quinocide), PA0 4. the biguanides with an inhibiting effect on dihydrofolic acid reductase (e.g. chloroproguanil, cycloguanil, proguanil), PA0 5. the diaminopyrimidines (e.g. pyrimethamine), PA0 6. the quinine salts. PA0 1. causal prophylactic substances effective against primary tissue stages, PA0 2. active substances directed against relapses or recurrences and effective against latent tissue stages, PA0 3. blood schizonticides, PA0 4. gametocytocides and PA0 5. sporonticides.
In addition to these groups, sulphones such as dapsone, sulphonamides, sulphanilamides and antibiotics such as tetracycline are also used as antimalarial agents.
Depending on their mode of activity the known antimalarial agents can be divided into the following categories:
The first group includes, for example, proguanil, pyrimethamine and primaquine and the derivatives thereof and possibly also sulphanilamides, sulphonamides and tetracyclines. For the second group, 8-aminoquinolines such as primaquine and its analogues and derivatives are available, for example, as well as floxacrine, cycloguanil, dapsone and quinazolines. Substances active against the blood schizonts, the third category, include in particular 4-aminoacridines such as mepacrine and the 4-aminoquinolines such as chloroquine or chloroquinesulphate, quinine, amodiaquine and mepacrine, mefluquine and related compounds such as halofantrene, as well as pyrimethamine, proguanil, primaquine and the sulphanilamides and sulphonamides, particularly in conjunction with pyrimethamine.
Other substances which may be considered are the sesquiterpene lactones based on the compound artemisinine and the semisynthetic derivatives thereof such as artesunate and artemether as well as piperaquine, hydroxypiperaquine, pyronaridine, halofantrene and, generally, the biguanides and quinine salts.
The schizonticides mentioned above are effective against the gametocytes of, for example, P. vivax, P. malariae or P. ovale, but not against the mature gametocytes. The 8-aminoquinolines such as primaquine and quinocide are also effective against the gametocytes. Proguanil, primaquine and pyrimethamine may be mentioned as sporonticidal agents. Other known antimalarial agents are: chloroproguanil, cycloguanil (e.g. as a salt of embonic acid), pamaquine, plasmocide, totaquine, spirogermanium, febrifugine, brusatol, bruceine-A, bruceine-B, bruceine-C, yadanziolide-A, tebuquine, enpirolin, eurycomanone, 3-(4-imidazolyl)-2-(pivaloylamido)propionylhydrazide, cinchonidine; cucurbitacine, tripynadine, 5-ethylthioribose, arteether (ethylether analogues of artemether), artenilic acid, pyrexol, atalaphillinine, diformyldapsone, bruceantine, nitroquine, octanoylprimaquine, pyrimethamine plus sulfadoxine, hivernine, dabequine, artelinic acid, mefloquinquinate, halfantrin-beta-glycerophosphate, nimbolide, sergeolide (quassinoid of Picrolemma pseudocoeffea), simalikalactone-D, fluoroquine, fluorenmethanol, isouramil, cycloleucine, acedapsone (diacetyldapsone), gentiopicrine, amquinate (amquinolate), endochine, pentaquine, isopentaquine, methylchloroquine, amopyroquine, quinine, hydroquinine (dihydroquinine), dimeplasmine, azacrine, diapromine, menoctone, cycloquine (haloquine), lapinone, aristoquine, cloguanamil, clociguanil, brindoxime, cinchonine, tripiperaquine, 3-hydroxy-2-(4-(4-phenyl)-cyclohexyl)-1,4-anthraquinone, aminodiaquine, 4-methyl-5-n-pentoxyprimaquine, 4-methyl-5-n-hexoxyprimaquine, 2-(4-(4-chlorophenyl)-cyclohexyl)-3-hydroxy-1,4-naphthalenedione, gossypol derivatives, halofantrine (1,3-dichloro-.alpha.-(2-(dibutylamino)ethyl)-6-(trifluoromethyl)- 9-phentantrene-methanol), cinchona alkaloids (e.g. in the combination quinine, quinidine, cinchonine), N,N'-bis(3-((phenylmethyl)amino)propyl)-1,8-octanediamine, N,N-bis(3-((phenylmethyl)amino)-propyl)-1,7-diaminoheptane, selenium-analogues of 2-acetyl and 2-propionyl-pyridinethiosemicarbazones, tebuquine, 2,6-bis(1-piperidinylmethyl)-4-((7-(trifluoromethyl)-4-quinolinyl)amino)-p henol, primary phosphoric acid esters of 4'-chloro-5-(1,1-dimethylethyl)-3-(((1,1-dimethylethyl)amino)methyl)-(1,1' -biphenyl-2-ol, N4-(2,6-dimethoxy-4-methyl-5-(3-trifluoromethyl)-phenoxy-8-quinolinyl)-1,4 -pentanediamine, N,N-diethyl-N'-(6-methoxy-4-methyl-8-quinolinyl)-1,6-hexanediamine, 5-(N-aryl-tropan-3-yl)-and 5-(piperidin-4-yl)-2,4-diamino-pyrimidine, 4'-amino-4-n-propylamino-2-methyl-diphenylsulphone, 5-ethylthioribose, riboflavin-analogues,1-(3-(2,4-dichlorophenoxy)-1,6-dihydro-6,6-dimethyl-1 ,3,5-triazine-2,4-diamine as the monohydrobromide, 1,6-dihydro-6,6-dimethyl-1-(3-(2,4,5-trichlorophenoxy)-propoxy)-1,3,5-tria zine-2,4-diamine as the monohydrochloride, trans-2-(4-(1,1-dimethylethyl)-cyclohexyl)-3-hydroxy-1,4-naphthalenedione, enpiroline, mirincamycin, tripynadine, 3-(4-imidazolyl)-2-(pivaloylamido)propionylhydrazide, 2-acetylpyridinethiosemicarbazones and the pyrrolidine derivatives thereof.
However, the use of these substances on their own or in conjunction with one another has the disadvantage that they achieve only a preventive or only temporary effect and the pathogens in question develop resistance more or less quickly; furthermore, many of these compounds have a toxic effect or are effective only in toxic concentrations (Peters, W, Br. Med. Bull. 38:187-192, (1982); Young et al., Am. J. Trop. Med. Hyg. 10:317-320 (1961); Bygbjerg, et al., Lancet 1:21-26 (1983); Schmidt, L. H., Antimicrob. Agents Chemother 16:475-485 (1979); Bruce-Chwatt, L. J. Essential malariology, W. Heinemann Medical Books Ltd., London, (1980)).
Many of these compounds have undesirable side effects or can be administered only to certain groups of people; furthermore, the very short plasma half-life of some of these substances prevents reasonable prophylactic use (Bruce-Chwatt et al., "Chemotherapy of Malaria" (2nd ed.) WHO, Geneva (1981); Colbourne, M. J., Comm. Dis. Rep. 35:3-4 (1983); Jiang et al., Lancet 2:285-288 (1982)).
In view of the increasing resistance to the compounds mentioned above, various combinations of these substances have been used, e.g. pyrimethamine with sulphadoxine (Doberstyn et al., Am. J. Trop. Med. Hyg. 25:14-19 (1976); Hall et al., Br. Med. J. 2:15-17 (1975); Merkli et al., Ann. Trop. Med. Parasit. 74:1-9 (1980)).
However, such combinations have not solved the problem of drug resistance and in addition complications have arisen caused by side effects (Hurwitz et al., Lancet 1:1068-70 (1981); Phillips et al., Lancet 1:300-302 (1984); Bjorkman et al. Trans. R. Soc. Trop. Med. Hyg. 84:177-180 (1990)).
In addition to the use of antimalarial substances of this kind it has been proposed to treat malaria infection prophylactically by immunization or vaccination.
However, the use of various preparations from the different plasmodial stages (sporozoites, merozoites, schizonts, gametes) has produced unsatisfactory results, particularly as the result of undesirable autoimmune reactions and non-specific immune responses (Trager et al., Parasite Immun. 5:255 (1983); Wernsdorfer, W. H., Bull, WHO 59:335 (1981)). Hitherto, an ideal vaccine has not become available (Young, et al. TIBTECH 6:63-68 (1988)).
In addition to the above-mentioned processes, the use of interferon, e.g. interferon-gamma (IFN-.gamma.), has been proposed both for vaccination (Playfair et al., Clin. Exp. Immunol. 67:5-10 (1987); Heath, et al., Immunol. 67:520-524 (1989)), and also for therapeutic treatment (Bienzle et al., Acta Tropica 45:289-290 (1988); Masheshwari et al., Infect. Immun. 53:628-633 (1986); Ferreira et al., Science 232:881-883 (1986); Clark et al., J. Immunol 139:3493-3496 (1987); Shear et al., J. Immunol. 143:2038-2044 (1989)).
In the former case, IFN-.gamma. acted as an adjuvant in conjunction with a suitable antigen; in the second case, although the development of the disease was slowed down in prophylactic use, therapeutic application, i.e. post infectionem, was less effective and was unable to inhibit the multiplication of parasites sufficiently. The combined prophylactic and therapeutic application of IFN-.gamma. had only a cumulative effect. There was no successful treatment in the sense of curative effect in any of the cases since all the animals (mice) died from the malaria infection when treated by any of the three methods, irrespective of how long the treatment lasted and with what dosages the animals were treated (Bienzle et al. (1988), loc. cit.).
In U.S. Pat. No. 4,915,941 it is proposed to use IFN-.gamma. in conjunction with an antimalarially active substance for preventing malaria infection, in which the administration of this combination does not extend beyond the prepatent phase (liver phase). During this phase it is not possible to diagnose the malaria.